KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer.
KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer.
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DOI：
10.1038/bjc.2015.165
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发表时间：
2015-06-09
影响因子：
8.8
通讯作者：
Rakha EA
中科院分区：
文献类型：
--
作者：
Alshareeda AT;Negm OH;Green AR;Nolan CC;Tighe P;Albarakati N;Sultana R;Madhusudan S;Ellis IO;Rakha EA
人们认识到，大分子核输入的调节在改变细胞表型和癌变中起作用。我们和其他人已经注意到，乳腺癌（BC）中DNA损伤反应（DDR）蛋白的异常亚细胞定位与功能丧失表型相关。本研究旨在探讨核细胞质转运蛋白核丝蛋白α-2 （KPNA2）的生物学和临床意义，及其在BC中控制DDR蛋白亚细胞定位的作用。采用免疫组织化学方法对大量（n=1494）、特征明确的早期浸润性BC患者进行了KPNA2蛋白检测，并进行了长期随访。KPNA2的表达与DDR关键蛋白的亚细胞定位相关，这些蛋白包括BRCA1、RAD51、SMC6L1、γH2AX、BARD1、UBC9、PIAS1和CHK1。高水平的KPNA2不仅与这些蛋白的细胞质定位有关，而且与它们的低/阴性核表达有关。KPNA2阳性表达与雌激素受体阴性和三阴性表型相关。生存分析显示KPNA2与预后不良相关（P<0.0001），但这种影响并非独立于其他预后变量。这项研究为BC中DDR机制的复杂性提供了进一步的证据，并且KNPA2在DDR蛋白的异常亚细胞定位和随后的功能受损中起作用。
It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin α-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC. A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry. KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, γH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P<0.0001), but this effect was not independent of other prognostic variables. This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.